{
  "abstract": "INTRODUCTIONWhether APOE {varepsilon}4 modifies relationships between subclinical cardiac phenotypes and brain structure is unknown.\n\nMETHODSIn Framingham Heart Study Offspring participants, we related antecedent echocardiographic remodeling (Examinations 4-6) to repeated brain MRI, and cardiac magnetic resonance phenotypes to regional cortical morphometry, testing cardiac x APOE {varepsilon}4 interactions with false-discovery-rate (FDR) correction and permutation testing of the regional screen.\n\nRESULTSAPOE {varepsilon}4 modified the association between antecedent left atrial (LA) remodeling and subsequent lateral ventricular expansion ({beta}=-0.00858, P=1.45x10-, q=0.0023; N=1,305; 3,787 MRI observations), the only FDR-significant result of 16 longitudinal tests, including with participant-specific MRI-time slopes (q=0.034); it weakened when intracranial volume x MRI time was modeled. Four regional ventricular cardiac x APOE {varepsilon}4 interactions met within-family FDR criteria, but their number was consistent with chance (permutation P=0.70). Maximum LA volume index showed an APOE {varepsilon}4-dependent association with left middle-occipital cortical-thickness variability (whole-brain q=0.017; permutation P=0.041) that persisted after ventricular adjustment. Cardiac phenotypes and trajectories showed no FDR-significant APOE {varepsilon}4-dependent associations with plasma A{beta}42/40, p-tau181, GFAP, or NfL, and adjustment for these biomarkers changed the regional interactions by at most 3.2%. Allen Human Brain Atlas data showed cholesterol-biosynthesis enrichment in the right superior frontal cortex, implicated by the LV end-systolic volume interaction, but without convergent pathway evidence.\n\nDISCUSSIONAPOE {varepsilon}4 modified atrial-brain relationships, with the strongest evidence linking antecedent atrial remodeling to later ventricular expansion. Replication with prespecified models is needed.\n\nHighlightsO_LIAPOE {varepsilon}4 modified how left atrial remodeling related to later brain ventricle growth. C_LIO_LIIt was the only FDR-significant result of 16 tests and persisted with random slopes. C_LIO_LIIn {varepsilon}4 carriers, larger LA volume tracked lower occipital thickness variability. C_LIO_LIThis atrial-cortical association was independent of LV mass and ejection fraction. C_LIO_LIExploratory: HbA1c related to LV end-diastolic volume differently by APOE {varepsilon}4 status. C_LI",
  "abstract_shown": true,
  "affiliations": [
    "Duke Univ Medical Center"
  ],
  "article_type": "PUBLISHAHEADOFPRINT",
  "arxiv": null,
  "author_total": 4,
  "authors": [
    {
      "affs": [
        0
      ],
      "name": "A. Badea"
    },
    {
      "name": "J. Xu"
    },
    {
      "name": "D. T. Laskowitz"
    },
    {
      "affs": [
        0
      ],
      "name": "C. T. Badea"
    }
  ],
  "bibtex": "https://research.draconitic.com/paper/5dtw69krj0r6f.bib",
  "cited_by": 0,
  "doi": "10.64898/2026.10.14.26365550",
  "fulltext_url": "https://www.medrxiv.org/content/10.64898/2026.10.14.26365550v1.full",
  "id": "5dtw69krj0r6f",
  "issns": [],
  "landing_url": "https://www.medrxiv.org/content/10.64898/2026.10.14.26365550v1",
  "language": null,
  "licence": "CC-BY-ND",
  "licence_label": "CC BY-ND",
  "licence_source": "article",
  "licence_url": "https://creativecommons.org/licenses/by-nd/4.0/",
  "metadata_licence": null,
  "native_subjects": [
    [
      "medrxiv",
      "neurology"
    ],
    [
      "openalex",
      "2738|Dementia and Cognitive Impairment Research"
    ]
  ],
  "openalex": "W7222993150",
  "pdf_url": "https://www.medrxiv.org/content/10.64898/2026.10.14.26365550v1.full.pdf",
  "pmcid": null,
  "pmid": null,
  "published": "2026-10-14",
  "publisher": null,
  "ris": "https://research.draconitic.com/paper/5dtw69krj0r6f.ris",
  "sources": [
    {
      "first_seen": "2026-10-30T12:21:20Z",
      "native_id": "10.64898/2026.10.14.26365550",
      "source": "medrxiv",
      "url": "https://www.medrxiv.org/content/10.64898/2026.10.14.26365550v1"
    }
  ],
  "subjects": [
    {
      "field": "medicine",
      "origin": "medrxiv:neurology",
      "subfield": "neurology"
    }
  ],
  "title": "APOE ε4 Modifies the Association of Left Atrial Remodeling With Brain Aging",
  "title_text": "APOE ε4 Modifies the Association of Left Atrial Remodeling With Brain Aging",
  "type": "preprint",
  "updated_at": "2026-10-30T12:21:20Z",
  "url": "https://research.draconitic.com/paper/5dtw69krj0r6f",
  "venue": "medRxiv",
  "versions": []
}